WO2004101772A2 - Cellule nerveuse - Google Patents

Cellule nerveuse Download PDF

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Publication number
WO2004101772A2
WO2004101772A2 PCT/EP2004/005233 EP2004005233W WO2004101772A2 WO 2004101772 A2 WO2004101772 A2 WO 2004101772A2 EP 2004005233 W EP2004005233 W EP 2004005233W WO 2004101772 A2 WO2004101772 A2 WO 2004101772A2
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WIPO (PCT)
Prior art keywords
stem cells
neural stem
cells
asct2
cell population
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PCT/EP2004/005233
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English (en)
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WO2004101772A3 (fr
Inventor
Andreas Bosio
Harold Cremer
Sandra Pennartz
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Memorec Biotec Gmbh
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Priority claimed from EP03025506A external-priority patent/EP1529838A1/fr
Application filed by Memorec Biotec Gmbh filed Critical Memorec Biotec Gmbh
Publication of WO2004101772A2 publication Critical patent/WO2004101772A2/fr
Publication of WO2004101772A3 publication Critical patent/WO2004101772A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0618—Cells of the nervous system
    • C12N5/0623—Stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2503/00—Use of cells in diagnostics

Definitions

  • the present invention relates to neural stem cells.
  • Multipotent neural stem cells represent the starting point for the generation of the myriad of diverse neuronal and glial cells, which make up the vertebrate nervous system (Williams et al., 1991) (Davis and Temple, 1994) (Weiss et al., 1996).
  • NCS Multipotent neural stem cells
  • NCS embryonic stem
  • NSC NSC can be derived from the very patient and thus do not provoke rejection by the immune system after grafting, and ii) that their isolation is ethically unobjectionable.
  • NSC are multipotent; they are at least able to differentiate to astrocytes, oli- godentritic cells and neurons.
  • Johansson et al. described ependymal cells along the lumen of the adult ventricular zone with features characteristic of multipotent stem cells (Johansson et al,, 1999), while Doetsch et al. identified a subpopulation of astro- cytes in the subventricular zone (SVZ, also known as subependymal zone) as NSC (Doetsch et al., 1999).
  • SVZ also known as subependymal zone
  • NSC Doetsch et al., 1999
  • a further object is to provide a medicament comprising the cell population of the present invention.
  • NCS can be considered as a multipotent differentiation intermediate between pluripotent ES cells and lineage-restricted, polysialylated NCAM ex- pressing (PSA + ) neuronal precursors. These two cell populations represent the developmental stages immediately up-stream and down-stream of NCS, respectively.
  • PSA + polysialylated NCAM ex- pressing
  • PSA + neuronal precursor cells were isolated from the adult mouse brain by fluorescent activated cell sorting (FACS) for transcriptome analysis (Pennartz et al., 2004).
  • FACS fluorescent activated cell sorting
  • Bruce-4 ES cells were chosen for the second SAGE library because they are derived from the inbred mouse strain C57BL/6J (Kontgen, 1993) that was used for PSA + cell isolation. Bruce-4 ES cells have been used in many gene tar- geting experiments showing excellent germ line transmission, which proves their pluripotent state. Prior to the RNA isolation of ES cells, the ratio of ES cells to contaminating fibroblasts was reduced from 60: 1 after initial plating to 80: 1 (1.25%).
  • SAGE Serial Analysis of Gene Expression
  • a SAGE library for adult total brain (ATB) was prepared.
  • the selection criterion for potential NSC markers was the following expression pattern: high expression in ES cells, low or no expression in PSA + precursors and ATB.
  • the candidate genes were further analyzed using in situ hybridizations to determine if their cellular localization is compatible with the localization of neurogenic areas, the SVZ and the hippocampus.
  • ES cells, NSC, PSA + cells and ATB are shown in a hierarchical order in terms of developmental potential starting with the greatest one on the left. All cell types are ac- cessible and can be isolated homogeneously, except for the NSC because of a lack of marker genes. Given that there is an overlap in the genetic programs of ES cells and NSC, a group of genes that are highly expressed in ES cells and downregulated or absent in PSA + cells and ATB should contain a subset of genes which are also expressed by the vanishingly small number of stem cells in the brain.
  • PSA + neuronal precursors are permanently generated in the SVZ lining the lateral ventricle. From here, they migrate along a well-defined pathway, the rostral migratory stream (RMS), into the olfactory bulb (OB), (Altman, 1969; Lois and Alvarez-Buylla, 1994; Luskin, 1993). Expression of PSA-NCAM is found exclusively on these migrating precursors in the adult mouse brain. Therefore, a specific antibody, the ⁇ -PSA mAb menB (1: 100) (Rougon et al., 1986), allowed the pure isolation of this cell population by FACS ( Figure 2). SAGE analysis for PSA + cells and ES cells
  • SAGE is based on the generation of short DNA. segments -15 bp SAGE tags- at defined positions close to 3' termini, allowing the assignment of these tags to the corresponding individual transcripts (Blackshaw et al., 2001; Velculescu et al., 1995).
  • SAGE was performed for PSA + cells as well as for C57BL/6J derived ES cells (Bruce-4) (Kontgen et al., 1993) (Tab. 1) (Pennartz et al., 2004).
  • the mapping of SAGE tags to UniGene and Swissprot is consistent with that observed in other SAGE databases (Gunnersen et al., 2002) ( Figure 3). Since SAGE analysis dis- plays the expression level of genes by absolute tag numbers, different SAGE projects can be directly compared.
  • the other reference SAGE library contained tags from adult total brain (ATB), i.e. mature neuronal and glial cells. These identified genes have unambiguous identification numbers provided for example under the name "SAGEmap" from the National Centre for Biotechnology Informa- tion (NCBI) accessable under www.ncbi.nlm.nin.gov/sage.
  • Table 2 Genes coding for cell surface proteins which represent potential NSC markers. The selection of these genes was based on significantly differential upregulation (p ⁇ 0.05) and 10-fold expression in ES cells versus PSA + cells and ATB according to the SAGE data. In cases, where several tags belong to one transcript, the main tag is shown with the number of different tags indicated in parentheses. Total tag numbers are normalized to 100,000.
  • EBs Embryoid bodies
  • NSC marker genes should label only single cells in the SVZ of adult mice. Since adult NSC can be viewed as remnants from brain development, a decrease in the number of brain cells expressing a potential marker gene would be expected from the time around birth to adulthood (Pevny and Rao, 2003).
  • In situ hybridizations were used to analyze the expression of the potential NSC markers (Tab. 2) in EBs and secondary neurospheres.
  • Antisense and sense (negative control) digoxigenin-labeled RNA probes were generated by in vitro transcription for each candidate.
  • EBs were grown in culture for 24 h.
  • Neurospheres were produced from dissected brain tissue containing the SVZ of P3 or P4 mice.
  • Primary neurospheres were grown for 5-7 days. To ensure that the neurospheres had the capability of self-renewal, they were dissociated to produce secondary neurospheres.
  • EBs and secondary neurospheres were fixed, frozen and cryostat sections were produced.
  • the SAGE tag "CCCCACCCCAC” had been assigned to CD8 antigen due to a falsely annotated EMBL sequence in the corresponding UniGene cluster. Recently, the correct UniGene cluster Mm.153963 KIAA0152 was discovered. This is a further potential marker, which could be used instead of ASCT2 to identify NSC.
  • RIKEN 2610033C09 The expression of RIKEN 2610033C09, ASCT2 and Frz-7 was examined in adult mouse brain.
  • RIKEN 2610033C09 staining was observed not only in the SVZ but also in the entire brain for different hybridization conditions (data not shown).
  • Frz-7 neither immunofluorescence nor the Vectastain ABC System produced labeling in mouse brain cryosections (data not shown).
  • ASCT2 is a NSC marker.
  • ASCT2 (also known as ATB 0 , SLC1A2, SLC1A7) is a neutral amino acid transporter, which was cloned from mouse testis (Utsunomiya-Tate et al., 1996). This transporter is part of the ASC system that is responsible for Na + -dependent transport of L-alanine, L-serine, and L-cysteine (Palacin et al., 1998).
  • ASCT2 participates in the glutamate-glutamine cycle which transfers glutamine between astrocytes and neurons (Broer and Brookes, 2001) and was found to mediate the L-isomer-selective transport of L-aspartic acid at the brain-blood barrier (Tetsuka et al., 2003).
  • a polyclonal antibody made in rabbit against the human ASCT2 protein is already available (Cat. num. AB5468, Chemicon).
  • the subject matter of the present invention is a cell population comprising at least 5% neural stem cells, said stem cells being characterized by an expression of genes identified by a SAGE tag mentioned in Table 2, especially by an expression of ASCT2 or KIAA0152.
  • the cell popula- tion comprises at least 10% of these neural stem cells, preferably at least 25%, more preferably more than 50%. Higher purities are preferred even up to 90 or 95% purity.
  • the cells are derived from rodents, e.g. mouse or rat. These cells are specially useful for further research.
  • the cells are derived from human. These cells are specially useful for diagnostic and development of medicaments.
  • Neural stem cells are obtainable by isolating them for example from brain. While embryonic stem cells are, by definition, localized in the inner cell mass of the embryo, the neural stem cells are present in the adult organism and localized in the nervous system. While ES cells and populations of differentiated cells derived from them were shown to form teratomas when introduced into the organism, neurospheres have not been observed to form teratomas and therefore NSC are unlikely to do so.
  • a further part of the invention is a method for isolating the cell population of the present invention comprising the following steps: a) taking a sample from nervous tissue, preferably brain b) isolating neural stem cells expressing ASCT2 or a) differentiating embryonic stem cells to neural stem cells, b) isolating neural stem cells expressing ASCT2 or a) trans-differentiating of adult none-neural stem cells to neural stem cells, b) isolating neural stem cells expressing ASCT2 or a) differentiating of adult neural precursor cells to neural stem cells, b) isolating neural stem cells expressing ASCT2 or a) differentiating of immortalised cells of neural stem cells, b) isolating neural stem cells expressing ASCT2 or a) producing neurospheres in culture, b) isolating neural stem cells expressing ASCT2.
  • KIAA0152 could be used as a marker.
  • a further embodiment of the present invention is a medicament comprising the cell population of the present invention.
  • a medicament can be used to treat neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, injury of the brain, stroke, birth defects of the brain.
  • a further embodiment is a monoclonal antibody directed against ASCT2 or KIAA0152.
  • This antibody can be a murine antibody directed against the murine protein.
  • Further embodiment is a monoclonal antibody directed against human ASCT2 or KIAA0152.
  • Figure 1 shows the selection strategy for potential NSC cells
  • FIG. 2 shows the isolation of PSA + neuronal precursors from the adult forebrain.
  • a-PSA mAb specifically recognizes PSA-NCAM on the surface of the imma- ture neuronal precursors in the RMS (a).
  • Use of this antibody permitted the isolation of a pure population of PSA + cells by FACS.
  • Rl marks the population of living cells (b) from which PSA + cells are selected in Ml by subtracting the autofluores- cence of the cells and the non-specific labeling of the secondary a-IgM antibody (c). Total yields of PSA + cells and RNA from several FACS experiments (d). Scale bar: 25 ⁇ m.
  • Figure 3 shows the mapping of (a) PSA + cell SAGE tags and (b) ES cell SAGE tags to UniGene clusters and SwissProt.
  • Figure 4 shows in situ hybridizations with antisense and sense probes for potential NSC markers in undifferentiated embryoid bodies. Only for RIKEN 2610033C09 (oP237G07), ASCT2 (OP011E02) did the antisense probe produce a stronger staining than the corresponding sense probe. Hybridization conditions: Ifitml (OP219H04): 45°C, 1000 ng/ml; RIKEN 2610033C09 (oP237G07), ASCT2 (oP011E02), Gap junction protein beta3, Connexin31 (oPHD09), Eva, epithelial V-like antigen (oP237H04): 50°C, 800 ng/ml. Scale bar 40 ⁇ m.
  • Figure 5 shows in situ hybridizations with antisense and sense probes for potential NSC markers in secondary neurospheres.
  • the hybridization of the antisense probe resulted in a stronger staining than the corresponding sense probe only in the case of RIKEN 2610033C09 (oP237G07) and ASCT2 (oP011E02).
  • Hybridization conditions Ifitml (oP219H04): 45°C, 1000 ng/ml; RIKEN 2610033C09 (oP237G07), ASCT2 (oP011E02), Gap junction protein beta3, Connexin31 (OP11D09), Eva, epithelial V-like antigen (oP237H04): 50°C, 800 ng/ml. Scale bar 40 ⁇ m.
  • Figure 6 shows in situ hybridization with the antisense probe for ASCT2, in secondary neurospheres under more stringent conditions (50°C, 600ng/ml) shows that occasionally few cells stand out from the others. Scale bar 25 ⁇ m.
  • Figure 7 shows in situ hybridization for ASCT2 in the mouse forebrain.
  • the ASCT2 antisense probe produces a specific staining in the majority of the cells in the first cell layers surrounding the lateral ventricle of P3 mice (a). In P14 mice, relatively less cells are labeled creating a spot-like staining pattern restricted to the SVZ and the beginning RMS (b).
  • LV lateral ventricle
  • RMS rostral migratory stream
  • SP septum
  • ST striatum.
  • Figure 8 shows in situ hybridization with the ASCT2 antisense probe at the lateral ventricle in P14 mouse forebrain.
  • In situ hybridization for ASCT2 labels single cells and small groups of cells within the SVZ and the RMS while no staining is observed on the septal side of the lateral ventricle.
  • LV lateral ventricle
  • RMS rostral migratory stream
  • ST striatum. Scale bar 25 ⁇ m.
  • Figure 9 shows in situ hybridization with the ASCT2 sense probe (negative control) at the lateral ventricle in P14 mouse forebrain.
  • the sense probe produces only background staining and confirms the specificity of the antisense staining.
  • LV lateral ventricle
  • RMS rostral migratory stream
  • ST striatum. Scale bar 25 ⁇ m.
  • Na(+)-dependent neutral amino acid transporter ATB(0) is a rabbit epithelial cell brush- border protein. Am J Physiol Cell Physio/. 281:C963-71.
  • LeX/ssea-1 Is Expressed by Adult Mouse CNS Stem Cells, Identifying Them as Nonependymal. Neuron. 35:865.
  • Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 97:703-16.
  • Na(+)-dependent neutral amino acid transporter ATB(0) is a rabbit epithelial cell brush-border protein

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Abstract

Cette invention concerne une population cellulaire comprenant au moins 5 % de cellules souches nerveuses, lesdites cellules étant caractérisées par une expression de ASCT2.
PCT/EP2004/005233 2003-05-14 2004-05-14 Cellule nerveuse WO2004101772A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP03010786.6 2003-05-14
EP03010786 2003-05-14
EP03025506.1 2003-11-06
EP03025506A EP1529838A1 (fr) 2003-11-06 2003-11-06 Cellules précurseurs et cellules souches neurales

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WO2004101772A3 WO2004101772A3 (fr) 2005-03-31

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011087091A1 (fr) * 2010-01-15 2011-07-21 協和発酵キリン株式会社 Anticorps anti-asct2 (transporteur aminoacide systeme asc type 2)
US8268592B2 (en) 2008-07-17 2012-09-18 Kyowa Hakko Kirin Co., Ltd Anti-system ASC amino acid transporter 2 (ASCT2) antibody

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000052143A2 (fr) * 1999-03-05 2000-09-08 California Institute Of Technology Isolation et enrichissement de cellules neurales souches provenant d'un tissu non cultive sur la base de l'expression de marqueurs de surface cellulaire

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000052143A2 (fr) * 1999-03-05 2000-09-08 California Institute Of Technology Isolation et enrichissement de cellules neurales souches provenant d'un tissu non cultive sur la base de l'expression de marqueurs de surface cellulaire

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BR\ER A ET AL: "The astroglial ASCT2 amino acid transporter as a mediator of glutamine efflux." JOURNAL OF NEUROCHEMISTRY. NOV 1999, vol. 73, no. 5, November 1999 (1999-11), pages 2184-2194, XP002297643 ISSN: 0022-3042 *
BROER STEFAN ET AL: "Transfer of glutamine between astrocytes and neurons" JOURNAL OF NEUROCHEMISTRY, vol. 77, no. 3, May 2001 (2001-05), pages 705-719, XP002297644 ISSN: 0022-3042 cited in the application *
MORRISON SEAN J ET AL: "Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells" CELL, MIT PRESS, CAMBRIDGE, MA,, US, vol. 96, no. 5, 5 March 1999 (1999-03-05), pages 737-749, XP002149096 ISSN: 0092-8674 *
UCHIDA N ET AL: "Direct isolation of human central nervous system stem cells" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE. WASHINGTON, US, vol. 97, no. 26, 19 December 2000 (2000-12-19), pages 14720-14725, XP002223508 ISSN: 0027-8424 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8268592B2 (en) 2008-07-17 2012-09-18 Kyowa Hakko Kirin Co., Ltd Anti-system ASC amino acid transporter 2 (ASCT2) antibody
US8945870B2 (en) 2008-07-17 2015-02-03 Kyowa Hakko Kirin Co., Ltd DNA encoding an anti-system ASC amino acid transporter 2 (ASCT2) antibody
WO2011087091A1 (fr) * 2010-01-15 2011-07-21 協和発酵キリン株式会社 Anticorps anti-asct2 (transporteur aminoacide systeme asc type 2)
US8501180B2 (en) 2010-01-15 2013-08-06 Kyowa Hakko Kirin Co., Ltd Anti system ASC amino acid transporter 2 (ASCT2) antibody
US8673592B2 (en) 2010-01-15 2014-03-18 Kyowa Hakko Kirin Co., Ltd Anti system ASC amino acid transporter 2 (ASCT2) antibody
JP5812869B2 (ja) * 2010-01-15 2015-11-17 協和発酵キリン株式会社 抗システムａｓｃアミノ酸トランスポーター２（ａｓｃｔ２）抗体

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